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NIH SCIENTISTS HIGHLIGHT ROLE OF MACROPHAGES IN HIV
INFECTION |
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NIH SCIENTISTS HIGHLIGHT ROLE OF MACROPHAGES IN HIV
INFECTION
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| Researchers have known for years that HIV can infect
specialized immune system cells called macrophages, but new
research suggests these cells may play a larger role in HIV
infection than previously believed. In the current online
early edition of "Proceedings of the National Academy of
Sciences", scientists from the National Institute of
Allergy and Infectious Diseases (NIAID) report that
macrophages contain and continue to produce large amounts
of an HIV-like virus in monkeys even after the virus
depletes CD4+ T cells, the primary HIV target in infected
individuals. This discovery provides new insight on how
the virus might survive in the midst of antiretroviral
drugs and suggests new strategies for eliminating the virus
from the body.
"Our research suggests that macrophages are an
underappreciated reservoir of virus in HIV infection," says
study author Malcolm A. Martin, M.D., chief of NIAID's
Laboratory of Molecular Microbiology. "These cells become
infected immediately after exposure to HIV, are relatively
resistant to virus killing, and are able to produce lots of
new virus. Most currently available treatments target HIV
during its infection of T cells, but if the virus also
infects and accumulates in large amounts in macrophages,
additional drugs may be required."
Highly active antiretroviral therapy, or HAART, can reduce
HIV to undetectable levels in a person's blood, but the
virus usually bounces back when the drugs are stopped.
Because HIV enters and destroys CD4+ T cells early in
infection, many researchers believe those cells are the
most likely source of the rebounding virus. Several
studies have questioned that idea, however, leaving
scientists uncertain of the key reservoir for latent HIV.
Dr. Martin and colleagues studied SHIV, a specially
designed hybrid virus in monkeys, to see if macrophages
might be a major virus source.
SHIV strains do not exist in nature but can be generated in
the laboratory by combining the outer envelope proteins of
HIV with a core of simian immunodeficiency virus (SIV), a
closely related monkey retrovirus that also induces AIDS in
inoculated animals. SHIV infection in monkeys is an
extremely rapid and exaggerated model of HIV infection in
humans that allows scientists to address certain clinical
aspects of retrovirus biology that are difficult or
impossible to study in people. "SHIV viruses rapidly
deplete CD4+ T cells yet continue to grow to very high
levels in the animal, allowing us to look at where else the
virus might be hiding," explains Dr. Martin. "Our studies
would be impossible to do in people because natural HIV
infection does not deplete T-cell populations as quickly or
as completely."
Dr. Martin and his colleagues infected macaques with a
highly virulent SHIV strain and watched the virus as it
infected cells. SHIV rapidly entered the animals' CD4+ T
cells and quickly eliminated most of those cells from the
blood, lymph nodes and other tissues. The infected monkeys
continued to produce high levels of virus, however,
suggesting that SHIV also had infected another cell type.
When the researchers examined lymphoid organs such as lymph
nodes and spleen for the source of the remaining virus,
they found that 95 percent of the virus-producing cells
were macrophages and only 1 to 2 percent were T cells.
Anthony S. Fauci, M.D., director of NIAID, says this might
partially explain the results of studies conducted recently
by his laboratory and others. "When patients on HAART stop
their therapy, the virus that bounces back usually differs
from the latent virus in their CD4+ T cells, suggesting
another reservoir for HIV. If the SHIV model is giving us
a glimpse of what is happening with HIV in humans, it might
point to macrophages as an important reservoir of HIV in
humans receiving HAART."
Dr. Martin believes this information might change how
physicians treat HIV infections. Currently available drugs
designed to attack the virus in T cells do not eliminate
all of the virus in the body, particularly those in
macrophages. The researchers tested this idea by checking
whether a potent reverse transcriptase (RT) inhibitor could
control both the early T-cell and late macrophage stages of
the SHIV infection. RT inhibitors are antiretroviral drugs
and key components of HAART. The team first treated
macaques early in the infection, when SHIV was predominant
in CD4+ T cells. In this group of animals, the drug
readily and efficiently reduced virus levels and protected
the monkeys from any T-cell loss. However, when the RT
inhibitor was given only during the later macrophage phase
of infection, the drug had no effect.
"If we want to completely eliminate the virus, we need to
attack it everywhere it lives, not just in the T cells,"
says Dr. Martin. "Our studies suggest we need new classes
of antiretroviral agents that can target HIV during
infections of tissue macrophages. They potentially could
eliminate this reservoir of virus and obviously complement
currently available drugs."
The researchers plan to use the SHIV model to further
investigate the role of macrophages in HIV infections.
SHIV infection in monkeys provides an ideal opportunity to
study infected macrophages in a living animal, a better
alternative than the tissue culture experiments scientists
have used to date. Studies are under way to see how
macrophages respond to SHIV infection and how long these
infected cells can survive. The researchers also will test
additional drugs, which they hope eventually will include
new candidate antiretroviral compounds designed to stop
latent virus from rebounding.
NIAID is a component of the National Institutes of Health
(NIH). NIAID supports basic and applied research to
prevent, diagnose, and treat infectious and immune-mediated
illnesses, including HIV/AIDS and other sexually
transmitted diseases, tuberculosis, malaria, autoimmune
disorders, asthma and allergies.
A copy of this article is available online at
www.pnas.org/papbyrecent.shtml.
Press releases, fact sheets and other NIAID-related
materials are available on the NIAID Web site at
www.niaid.nih.gov.
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REFERENCE:
Igarshi T et al. Macrophages are the principal reservoir
and sustain high virus loads in Rhesus macaques following
the depletion of CD4+ T cells by a highly pathogenic SHIV:
implications for HIV-1 infections of man. "Proc Natl Acad
Sci" 98:658-63 (2001).
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